JP2651616B2 - Transdermal formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel transdermal absorption preparation. More specifically, the present invention relates to a transdermal preparation which is excellent in both transdermal absorbability and safety, and is effective for treating various diseases in which a desired pharmacologically active substance can be rapidly delivered to a local site or a systemic system through a circulatory system. It is about.

[Prior Art] In recent years, in the medical field, a transdermal therapeutic system (TTS) capable of delivering a desired pharmacologically active substance to the whole body through the skin and exhibiting a therapeutic effect over a long period of time has been developed. A transdermal therapeutic system using nitroglycerin or isosorbide dinitrate for treating angina, clonidine for treating hypertension, estradiol for treating climacteric disorders, etc. has been put to practical use.

However, such a transdermal therapeutic system has many advantages, such as avoidance of metabolism of pharmacologically active substances in the intestine and liver, reduction of side effects, and improvement of sustained drug efficacy. Since it has a barrier function against invasion, pharmacologically active substances whose blood concentration obtained by percutaneous absorption reaches the effective therapeutic range are extremely limited, and the pharmacologically active substances that can be used are limited. There is a disadvantage that it cannot be spared.

Therefore, various methods have been attempted to improve the transdermal absorbability of pharmacologically active substances. For example, methods such as prodrug formation and complex formation by modification of pharmacologically active substances, and iontophoresis for ionic pharmacologically active substances have been attempted, but all of these methods are not sufficient for individual pharmacologically active substances. There is a problem that it needs to be examined and requires a lot of time and a lot of investment. On the other hand, development of absorption enhancers that reduce skin barrier properties and improve transdermal absorption of pharmacologically active substances has also been actively conducted. The type is not so limited, and it is expected that many types can be used.

Examples of the absorption promoter include polar solvents such as dimethylsulfoxide, decylmethylsulfoxide, dimethylformamide, and dimethylacetamide; cycloalkanes such as azacycloheptan-2-one; isopropyl myristate; and isopropyl palmitate. Examples include surfactants such as esters of alcohols and carboxylic acids, glycols and sodium lauryl sulfate, and derivatives such as fatty acids, pyroglutamic acid and urea, which are natural moisturizing factors for skin. However, these absorption enhancers do not always sufficiently satisfy both the effect of promoting percutaneous absorption and the safety, and have a lag time in the percutaneous absorption of many pharmacologically active substances. It is disadvantageous in that it is large and it takes time for the pharmacological action to develop.

[Problems to be Solved by the Invention] Under such circumstances, the present invention is excellent in both percutaneous absorbability and safety, and rapidly delivers a desired pharmacologically active substance to a local site or a whole body through a circulatory system. The purpose of the present invention is to provide a percutaneous absorption preparation effective for treating various diseases which can be caused.

[Means for Solving the Problems] The present inventors have conducted intensive studies to develop a transdermal absorption preparation having the above-mentioned excellent characteristics, and as a result, pharmacological activity of limonene, which can be easily obtained from nature, has been confirmed. Focusing on the fact that it has a function to remarkably promote the transdermal absorption of a substance and is also excellent in safety, by including this limonene in a percutaneous absorption preparation at a predetermined ratio as a transdermal absorption enhancer It has been found that the object can be achieved, and the present invention has been completed based on this finding.

That is, the present invention provides a percutaneous absorption preparation containing limonene and a pharmacologically active substance, wherein the content of limonene is 0.1 to 30% by weight based on the total amount of the percutaneous absorption preparation. is there.

 Hereinafter, the present invention will be described in detail.

In the percutaneous absorption preparation of the present invention, limonene used as a percutaneous absorption enhancer has a right-handed body and a left-handed body, and d-limonene in the right-handed body is derived from citrus peels such as orange and lemon. It is the main component of the essential oil obtained, while l-limonene in the left rotator is contained in perilla oil and henopoi oil, and dl-limonene is contained in salamander oil and the like. There is no clear difference in the percutaneous absorption promoting effect of these limonene, and in the present invention, any of them can be used as a percutaneous absorption enhancer, but each has a different odor, When used as an additive, its odor is also an object of evaluation, and those that emit a foul odor are not preferred. From such a viewpoint, d-limonene having a lemon or orange smell is particularly preferable among the above-mentioned limonene.

The content of limonene in the transdermal absorption preparation of the present invention must be selected in the range of 0.1 to 30% by weight based on the total amount of the preparation. If the amount is less than 0.1% by weight, the effect of promoting percutaneous absorption is not sufficiently exhibited, and if it exceeds 30% by weight, no improvement in the effect is recognized for the amount, and skin irritation increases. In view of the effect of promoting percutaneous absorption and skin irritation, the content of limonene is preferably in the range of 1 to 5% by weight. It is good to choose appropriately according to.

Since limonene has high fat solubility and is hardly soluble in water,
It is preferable to use a pharmacologically acceptable organic solvent, a solubilizing agent such as pyrrolidone, or a surfactant in combination, or a suspension using an emulsifier or a dispersant.

The pharmacologically active substance used in the transdermal absorption preparation of the present invention is not particularly limited, and any pharmacologically active substance can be selected from conventionally known pharmacologically active substances. Examples of the pharmacologically active substance include steroidal anti-inflammatory agents such as prednisolone, dexamethasone, hydrocortisone, fluocinoloacetonide, betamethasone valerate, betamethasone dipropionate, indomethacin, diclofenac, ibfenac, ibuprofen, ketoprofen, flufenamic acid, mefenam Non-steroidal anti-inflammatory drugs such as acid, phenylbutazone, methyl salicylate, etc .; antihistamine drugs such as diphenhydramine, chlorpheniramine, promethazine, triperenamine, chlorpromazine, central nervous system drugs such as nitrazepam, diazepam, phenobarbital, reserpine, insulin, testosterone Hormonal drugs such as, methyltestosterone, progesterone, estradiol, clonidine, reserpine Anti-hypertension agent such as sulfuric acid guanethidine,
Cardiotonic agents such as digitoxin and digoxin, antiarrhythmic agents such as propranol hydrochloride, procainamide hydrochloride, adimarin, pindolol, coronary vasodilators such as nitroglycerin, isosorbide dinitrate, erythritol tetranitrate, papaverine hydrochloride, and nifedipine; Local anesthetics such as lidocaine, benzocaine, procaine hydrochloride,
Barbital, thiopental, phenobarbital,
Hypnotics and sedatives such as cyclobarbital, morphine,
Analgesics such as aspirin, codeine, acetanilide, aminopyrine, antibiotics such as penicillin, tetracycline, erythromycin, streptomycin, gentamicin; , Actinomycin, bleomycin, antineoplastic agents such as mitomycin, anti-diuretic agents such as hydrochlorothiazide, penflutide, reserpine, scopolamine,
Adrenergic blockers such as atropine, antiepileptic drugs such as nitrazepam and meprobamate, chlorzoxazone,
Antiparkinson drugs such as levodopa, sulfamines such as sulfamine, sulfamonomethoxine, sulfamethizole, and even vitamins, prostaglandins,
Examples include anticonvulsants, but are not limited thereto. These pharmacologically active substances may be used alone or in combination of two or more.

The percutaneous absorption preparation of the present invention, if desired, various pharmacologically acceptable additives within a range not to impair the purpose of the present invention,
For example, stabilizers, antioxidants, antioxidants, fragrances, fillers, or other transdermal absorption enhancers may be added.

There is no particular limitation on the mode of use of the transdermal absorption preparation of the present invention, and dosage forms conventionally used as external preparations, for example, ointments, creams, gels, lotions, liquids, sprays, cataplasms, tapes It can be used as an external preparation of any dosage form such as a preparation.

As base materials for the ointments and creams, for example, fatty oil, lanolin, petrolatum, paraffin, plastibase, glycols, higher fatty acids, higher alcohols and the like are used. If necessary, stabilizers, preservatives, emulsifiers, suspending agents and the like are added to these base materials. In the case of a lotion, for example, ethanol, glycerin, glycol or the like is used as a substrate, and in the case of a liquid, for example, ethanol, purified water, glycol or the like is used.

Further, as a base material of the poultice, for example, gelatin, sodium alginate, corn starch, tragacanth gum, natural polymers such as casein, methylcellulose,
Cellulosics such as ethyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose, starches such as dextran and carboxymethyl starch, and synthetic polymers such as polyvinyl alcohol, sodium polyacrylate, polyvinyl pyrrolidone, and polyvinyl ether are used. If necessary, these base materials are blended with, for example, humectants such as glycerin and propylene glycol, inorganic fillers such as kaolin, bentonite and zinc white, viscosity modifiers, pH regulators, antioxidants and the like. You.

Furthermore, examples of the adhesive used in the tape preparation and the patch preparation include acrylic, rubber, and silicone-based adhesives.These adhesives include a pharmacologically active substance or water and a pharmacologically active substance. The water-soluble polymer compound containing the pharmaceutically active substance can be dispersed to form a micro-reservoir type. Conversely, an adhesive containing a pharmacologically active substance can be dispersed with a poultice.

As the acrylic pressure-sensitive adhesive, as a main component, for example, an acrylate homopolymer, a copolymer containing two or more acrylate units, and a copolymer of acrylate and another functional monomer Those containing at least one selected from the above are used. Examples of the acrylate include butyl (meth) acrylate, pentyl (meth) acrylate, and (meth) acrylate.
Hexyl acrylate, heptyl (meth) acrylate, octyl (meth) acrylate,
Nonyl (meth) acrylate and decyl (meth) acrylate are exemplified. Examples of the functional monomer include hydroxyl group-containing monomers such as hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate, and amides such as (meth) acrylamide and dimethyl (meth) acrylamide. Group-containing monomers and the like.

This acrylic pressure-sensitive adhesive is generally roughly classified into a solvent type and an emulsion type, and the solvent type is usually composed of the acrylic polymer, a solvent, a cross-linking agent and a tackifier used as desired, and the like. As the system, methylol group condensation, ionic crosslinking, urethane crosslinking, epoxy crosslinking and the like are used. On the other hand, the emulsion type is usually composed of the acrylic polymer, an emulsifier, an aqueous solvent, a tackifier used as required, and the like.

As the rubber-based pressure-sensitive adhesive, as a main component, for example, selected from among natural rubber, polyisoprene rubber, polyisobutylene, polybutadiene rubber, styrene-butadiene-styrene block copolymer, styrene-isoprene-styrene block copolymer, and the like. A material containing at least one of these is used. If desired, a tackifier, a plasticizer, an antioxidant, a filler, and the like can be added to the rubber-based pressure-sensitive adhesive. Further, as a form, a solvent type or an emulsion type using the rubber latex is preferably used.

Further, as the silicone-based pressure-sensitive adhesive, a solvent-type pressure-sensitive adhesive containing, for example, polydimethylsiloxane or polydiphenylsiloxane as a main component, and further containing a tackifier, a plasticizer, a filler, and the like as desired is preferably used. .

These adhesives, as the tackifier to be blended as desired, for example, rosin resins, natural resins such as polyterpene resins, C ₅ based, C ₉ type, DCPD petroleum resins, coumarone-indene resin, A synthetic resin such as a xylene resin may be used.

The base material used for the tape preparation is, for example, a sheet or film made of a synthetic resin such as polyester, polyvinyl chloride, polypropylene, polyethylene, or polyurethane, a synthetic paper, or a cellulosic sheet or film, or a material made of various materials. Non-woven fabrics, woven fabrics, knitted fabrics and the like can be mentioned.

[Action] It is said that the barrier properties of the skin against exogenous substances depend on the structure of the stratum corneum. One of the reasons is, for example, that the permeability of the pharmacologically active substance is significantly increased by peeling off a tape or the like. In the stratum corneum, stratum corneum, which is a flattened protein, is layered, and the pharmacologically active substance passes through a transcellular route (Tanscellular route) that penetrates the cell and an intercellular route that passes through the intercellular space. Ra Root (Intercellu
lar route). These keratinocytes are composed of keratin and lipids. In the intercellular route, amphiphilic substances such as phospholipids form a lamellar layer, and a hydrophilic layer and a lipophilic layer are layered. The hydrophilic layer is in the form of clusters in which water molecules are aggregated. Both layers have high resistance to diffusion of other substances, and the barrier properties are said to be due to these tight structures.

Limonene has a particularly high affinity for lipids, and is thought to give fluctuations to the lipids, increase fluidity, reduce diffusion resistance, increase permeability of pharmacologically active substances, and act on lipids. Thus, it is presumed that this has a considerable effect on the structure of water molecules in the hydrophilic layer, and brings about an effect of improving permeability.

[Examples] Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Examples 1 and 2, Comparative Examples 1 to 3 Percutaneous absorption experiments of the pharmacologically active substance indomethacin were performed using male Wistar rats weighing 160 to 190 g.

The abdominal hair of the rat was depilated with an animal clipper, and a cylindrical glass cell having an inner diameter of 16 mm and a height of 10 mm was fixed with a biological adhesive.

Next, a gel ointment having the composition shown in Table 1 was prepared, and 1 g of the gel ointment was prepared.
Was applied. After application, blood was collected from the carotid artery over time, and the blood concentration of indomethacin was determined by high performance liquid chromatography. The relationship between the elapsed time and the blood concentration is the first
This is shown graphically in the figure.

Example 3, Comparative Example 4 A gel ointment having the composition shown in Table 2 was prepared using ketoprofen as a pharmacologically active substance, and a transdermal absorption experiment was carried out in the same manner as described above. FIG. 2 is a graph showing the relationship between the elapsed time and the blood ketoprofen concentration.

Example 4, Comparative Example 5 A gel ointment having the composition shown in Table 3 was prepared using diclofenac sodium as the pharmacologically active substance, and a transdermal absorption experiment was carried out in the same manner as described above. FIG. 3 is a graph showing the relationship between the elapsed time and the blood diclofenac sodium concentration.

As can be seen from FIGS. 1 to 3, the gel ointment of the present invention containing d-limonene is superior in percutaneous absorption of a pharmacologically active substance as compared with those containing no d-limonene. . In Comparative Example 3 containing 2% by weight of azone, the effect of improving percutaneous absorption was slightly observed, but the percutaneous absorption was much lower than that in Example 2 containing 2% by weight of d-limonene.

Example 5 A percutaneous absorption test of indomethacin was carried out in exactly the same manner as in Example 1 except that l-limonene was used instead of d-limonene in Example 1. The results were similar to those for d-limonene. A transdermal absorption promoting effect was observed.

Note that d-limonene has a preferable odor of lemon or orange, while l-limonene has a slightly unpleasant odor.

Reference Example 1 Various concentrations of ethanol solutions of d-limonene and azone (1-dodecylazacycloheptan-2-one) were prepared and used as samples.

The hair on the back of a white rabbit weighing about 1.5 kg was removed using an animal clipper, and after 24 hours, the sample was soaked in a patch test patch and applied, followed by patching in accordance with the Draize method. A test was performed to determine the skin primary irritation index. FIG. 4 shows the relationship between the d-limonene or azone concentration and the skin primary irritation index in grams.

From FIG. 4, it can be seen that d-limonene is clearly less irritating than Azone, and hardly irritates the skin when the concentration of d-limonene is 5% by weight or less. And d-limonene is 1,2% by weight
Since a remarkable transdermal absorption promoting effect is observed even when a small amount of is added, it can be judged that it is practical as a transdermal absorption enhancer.

Reference Example 2 A sensory test was conducted by five panelists on the odor of the compound known as a conventional transdermal absorbent and limonene shown in Table 4 and evaluated according to the following symbols.

: 1: 1 point No odor or favorable odor.

Δ: 2 points Low odor or slightly preferable (allowable) odor.

×: 3 points Slightly unpleasant odor.

XX: 4 points An unpleasant odor.

The score is a value obtained by dividing the evaluation of the odor into four grades of 1 to 4 (it is better that the score is small), having each panelist give a score, and rounding the average value.

Dicyclohexyl has a favorable odor like d-limonene, but the effect of promoting percutaneous absorption is d-limonene.
Inferior to limonene.

[Effects of the Invention] The percutaneous absorption preparation of the present invention contains limonene, which is excellent in both percutaneous absorption and safety, as a percutaneous absorption enhancer, thereby allowing a desired pharmacologically active substance to be passed through a local site or a circulatory system. Since it can be rapidly delivered to the whole body, it is extremely useful for treating various diseases.

[Brief description of the drawings]

FIGS. 1, 2 and 3 are graphs showing the relationship between the elapsed time of application and the concentration of the pharmacologically active substance in blood in examples of gel ointments of various compositions, respectively. FIG. 4 is a graph showing d- in an ethanol solution. It is a graph which shows the relationship between the concentration of limonene or azone, and a primary skin irritation index.

Claims (2)

(57) [Claims] (1) It contains limonene and a pharmacologically active substance, and the content of limonene is 0.1 to 3 based on the total amount of the transdermal absorption preparation.
A transdermal absorption preparation characterized by being 0% by weight. 2. The transdermally absorbable preparation according to claim 1, wherein the limonene is d-limonene.